Project Summary The development and progression of diabetes involves oxidative stress and inflammation that leads to disorders in multiple organs including the cardiac and skeletal muscle. However, it remains unknown whether inflammation induced cell death, known as pyroptosis occurs in cardiac and skeletal muscle of diabetics. Our preliminary data shows that diabetic mice have enhanced infiltration of monocytes, pro-inflammatory toll-like receptor 4, NLRP3 inflammasome, activated caspase-1 and increased pro-inflammatory cytokines in the heart as well as skeletal muscle. Treatment with the recombinant bone morphogenic protein-7 (BMP-7) decreased hyperglycemia, inflammation and improved cardiac and muscle function. Based on these preliminary data, we hypothesize that BMP-7 increases anti-inflammatory M2 macrophages decreases pyroptosis, thereby improving cardiac and skeletal muscle function in diabetes. We propose to test this hypothesis through the following aims. 1: Diabetes causes cardiac and skeletal muscle dysfunction through increase of inflammatory cytokines, activation of NLRP3 inflammasome and caspase 1 regulated pyroptosis. 2: Treatment with BMP-7 differentiates monocytes into anti-inflammatory M2 macrophages resulting in amelioration of pyroptosis and adverse cardiac and skeletal muscle remodeling in diabetic mice. 3: Chronic treatment with BMP-7 ameliorates diabetic complications through suppression of inflammatory pathways and pyroptosis in a translational rabbit model of diabetes. The proposed studies will be carried out in the well-established models of Type 1 and Type 2 diabetes. We expect to elucidate the critical role of pyroptosis in causing cardiac and skeletal muscle dysfunction and the beneficial role of BMP-7 therapy in diabetes. These studies have the promise for critical care of diabetic patients, because BMP-7 is clinically approved for the treatment of osteoporosis patients in Europe.